Abstract EN:

Diabetes mellitus represents a heterogeneous group of metabolic disorders characterized by sustained high blood glucose concentrations. Disease etiology is still poorly understood but involves both genetic and environmental factors. The main aim of this thesis was to identify and study genes responsible for monogenic forms of juvenile-onset insulin-dependent diabetes (JOD) in the Lebanese population. Due to the high rate of consanguinity and intra-population endogamy, the Lebanese population is particularly well suited to address the question of the responsibility of monogenic contribution to JOD. Using a family-based genetic study, we identified evidence of linkage near the WFS1 gene, responsible for Wolfram syndrome. We identified one frameshift mutation, the WFS1LIB mutation, which was associated with a delayed onset of optic atrophy (OA). The delayed onset of OA in WFS1LIB homozygous patients was family dependent and suggested the role of a modifier variant. Our results suggest that one common variant located in the 5' regulatory region of the WFS1 gene is associated with delayed onset of OA and decreased expression of WFSL After excluding ail genetically explained families, we identified evidence of linkage on chromosome 11. We selected the most plausible candidate gene and identified 3 mutations. We then used a siRNA-mediated knockdown approach in dispersed islets, INS-1E, and purified bêta cells and showed that gene deficiency resulted in increased cell death and decreased insulin expression. The last study concerns the genetic investigation of a diabetic Lebanese patient initially diagnosed as Wolfram Syndrome. Using linkage study and sequencing, we selected ALMS1, responsible for Alström Syndrome, in which we identified a novel splice mutation. In conclusion, monogenic forms of diabetes are likely to represent a significant subset of JOD cases, generally diagnosed as T1D, particularly in highly consanguineous populations such as Lebanon.